Mechanical loading is required to maintain bone mass in the adult skeleton. Removing this critical factor (i.e., disuse) precipitates a series of cellular events resulting in locally mediated bone resorption. However, the pathway by which the removal of mechanical loading is transduced into bone resorption is not understood. Recently, we have found that disuse induces osteocyte hypoxia within 24 hours of unloading. To our knowledge, this is the first in vivo observation of cellular hypoxia in response to altered mechanical loading of a tissue. Hypoxia is known to elicit a variety of profound cellular responses (e.g., cytoskeletal disruption). As osteocytes are ideally situated to monitor and respond to bone's mechanical environment, we suggest that disuse induced osteocyte hypoxia has the potential to initiate and/or mediate local bone resorption. Further, aging diminishes the ability of a cell to withstand hypoxia and may therefore amplify the resorptive process. Our general hypothesis is that daily mechanical loading of bone is required to inhibit osteocyte hypoxia. To examine this hypothesis, we will use the avian model of disuse osteopenia. In this model, we are able to expose the ulna to disuse or disuse superimposed with a daily loading regimen. Five specific aims are proposed in which we will demonstrate that: 1) disuse induced osteocyte hypoxia temporally precedes and is spatially related to intracortical resorption, 2) loading regimens that inhibit osteocyte hypoxia will also prevent disuse induced intracortical resorption, 3) age does not diminish the ability of a given loading regimen to inhibit osteocyte hypoxia, 4) a finite period of time exists in which loading must be re-initiated in order to successfully rescue bone from osteocyte hypoxia and resorption, and 5) age diminishes this window of opportunity. We believe that these tissue level experiments will support a cause and effect relation between mechanical loading and osteocyte hypoxia, and will determine whether this process is altered by aging. The data will thereby provide basic insight toward how osteocytes perceive and respond to mechanical stimuli within their native environment. Examining how this process is altered by aging will enhance our ability to successfully apply this information toward combating bone loss pathologies increasingly prevalent in our aging population.